利伐沙班杂质7(S-异构体)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 2-[(25)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A. Gutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and 4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water (9:1, 140 ml) is refluxed for 14 h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. The combined mother liquors are concentrated under reduced pressure and, after addition of a second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (2.84 g, 14.0 mmol), suspended in ethanol/water (9:1, 70 ml) and refluxed for 13 h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. Total yield: 10.14 g, 92% of theory. dissolves The precipitate (desired product) is filtered off washed three times with diethyl ether dried The combined mother liquors are concentrated under reduced pressure refluxed for 13 h (the precipitate dissolves The precipitate (desired product) is filtered off washed three times with diethyl ether dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 2-[(25)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A. Gutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and 4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water (9:1, 140 ml) is refluxed for 14 h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. The combined mother liquors are concentrated under reduced pressure and, after addition of a second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (2.84 g, 14.0 mmol), suspended in ethanol/water (9:1, 70 ml) and refluxed for 13 h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. Total yield: 10.14 g, 92% of theory. dissolves The precipitate (desired product) is filtered off washed three times with diethyl ether dried The combined mother liquors are concentrated under reduced pressure refluxed for 13 h (the precipitate dissolves The precipitate (desired product) is filtered off washed three times with diethyl ether dried

反应条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a four neck round bottom flask charged Isopropyl alcohol (135 ml), 4-(4-aminophenyl) morpholin-3-one (10 g), 2-[(2s)-oxiran-2yl methyl]-1H-isoindole-1,3(2H)dione ((11.6 g) and water (15 ml) at 25 to 30° C. Slowly heated the reaction mixture to reflux and maintained for 24 h at reflux temperature. Reaction mass is cooled to 25 to 30° C. after completion of the reaction. Reaction mass then maintained at 25 to 30° C. for 30 minutes. Finally obtained solid is filtered off and washed by isopropyl alcohol (25 ml) Slowly heated the reaction mixture to reflux maintained for 24 h at reflux temperature Reaction mass after completion of the reaction Reaction mass then maintained at 25 to 30° C. for 30 minutes Finally obtained solid is filtered off washed by isopropyl alcohol (25 ml)

反应条件: temp:27.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In a four neck round bottom flask charged Isopropyl alcohol (135 ml), 4-(4-aminophenyl) morpholin-3-one (10 g), 2-[(2s)-oxiran-2yl methyl]-1H-isoindole-1,3(2H)dione ((11.6 g) and water (15 ml) at 25 to 30° C. Slowly heated the reaction mixture to reflux and maintained for 24 h at reflux temperature. Reaction mass is cooled to 25 to 30° C. after completion of the reaction. Reaction mass then maintained at 25 to 30° C. for 30 minutes. Finally obtained solid is filtered off and washed by isopropyl alcohol (25 ml) Slowly heated the reaction mixture to reflux maintained for 24 h at reflux temperature Reaction mass after completion of the reaction Reaction mass then maintained at 25 to 30° C. for 30 minutes Finally obtained solid is filtered off washed by isopropyl alcohol (25 ml)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: In this case, 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)dione (II) is reacted with 4-(4-aminophenyl)-3-morpholinone (III) to give 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)-phenyl]amino}propyl)-1H-isoindole-1,3(2H)dione (V). Subsequently, (V) is converted with a phosgene equivalent into 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-1H-isoindole-1,3(2H)dione (VI). Elimination of the phthalimide protective group affords 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one (VII) which is finally reacted with 5-chlorothiophene-2-carbonyl chloride (IV) to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of N-[(2S)-oxiran-2-ylmethyl]-phthalimide (18.4 g, 90.6 mmol) and 2-mercaptobenzothiazole (15.8 g, 94.5 mmol) in EtOH (530 mL) was heated to reflux for 14.5 h. The reaction was then cooled and concentrated under reduced pressure. The crude mixture was crystallized from ethanol and filtered to provide N-[(2S)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide (25.5 g, 76%) as a solid. Data for N-[(2S)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide: 1H NMR (300 MHz, CDCl3) δ 7.88 (m, 2H), 7.75 (m, 4H), 7.45-7.26 (m, 2H), 5.15 (m, 1H), 4.42 (m, 1H), 4.08-3.88 (m,2H, 3.61 (m, 1H), 3.42 (m, 1H). was heated to reflux for 14.5 h The reaction was then cooled concentrated under reduced pressure The crude mixture was crystallized from ethanol filtered

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of N-[(2S)-oxiran-2-ylmethyl]-phthalimide (18.4 g, 90.6 mmol) and 2-mercaptobenzothiazole (15.8 g, 94.5 mmol) in EtOH (530 mL) was heated to reflux for 14.5 h. The reaction was then cooled and concentrated under reduced pressure. The crude mixture was crystallized from ethanol and filtered to provide N-[(2S)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide (25.5 g, 76%) as a solid. Data for N-[(2S)-3-(1,3-benzothiazol-2-ylthio)-2-hydroxypropyl]-phthalimide: 1H NMR (300 MHz, CDCl3) δ 7.88 (m, 2H), 7.75 (m, 4H), 7.45-7.26 (m, 2H), 5.15 (m, 1H), 4.42 (m, 1H), 4.08-3.88 (m,2H, 3.61 (m, 1H), 3.42 (m, 1H). was heated to reflux for 14.5 h The reaction was then cooled concentrated under reduced pressure The crude mixture was crystallized from ethanol filtered

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cold solution of (S)-1-oxiranylmethanol (5 g, 67.5 mmol) and phthalimide (9.9 g, 67.3 mmol) in tetrahydrofuran (200 mL) in ice bath was added triphenylphosphine (17.9 g, 68.2 mmol) and diethyl azodicarboxylate (12.3 g, 70.6 mmol). The mixture was stirred at 0° C. for 2 h and at ambient temperature for 48 h. The mixture was concentrated under vacuum, and the oily residue was purified by flash silica column chromatography, yielding the desired product (10.1 g) as pale yellow solid: Rf=0.51 in 1:1 EtOAc/hexane. 1H-NMR (CDCl3, 300 MHz): δ (ppm) 7.76-7.64 (m, 2H), 7.63-7.60 (m, 2H), 3.9-3.8 (dd, 1H), 3.70-3.65 (dd, 1H), 3.15 (m, 1H), 2.70-2.67 (dd, 1H), 2.58-2.55 (dd, 1H). The mixture was concentrated under vacuum the oily residue was purified by flash silica column chromatography

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a cold solution of (S)-1-oxiranylmethanol (5 g, 67.5 mmol) and phthalimide (9.9 g, 67.3 mmol) in tetrahydrofuran (200 mL) in ice bath was added triphenylphosphine (17.9 g, 68.2 mmol) and diethyl azodicarboxylate (12.3 g, 70.6 mmol). The mixture was stirred at 0° C. for 2 h and at ambient temperature for 48 h. The mixture was concentrated under vacuum, and the oily residue was purified by flash silica column chromatography, yielding the desired product (10.1 g) as pale yellow solid: Rf=0.51 in 1:1 EtOAc/hexane. 1H-NMR (CDCl3, 300 MHz): δ (ppm) 7.76-7.64 (m, 2H), 7.63-7.60 (m, 2H), 3.9-3.8 (dd, 1H), 3.70-3.65 (dd, 1H), 3.15 (m, 1H), 2.70-2.67 (dd, 1H), 2.58-2.55 (dd, 1H). The mixture was concentrated under vacuum the oily residue was purified by flash silica column chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A. Gutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and 4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water (9:1, 140 ml) is refluxed for 14 h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. The combined mother liquors are concentrated under reduced pressure and, after addition of a second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (2.84 g, 14.0 mmol), suspended in ethanol/water (9:1, 70 ml) and refluxed for 13 h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. Total yield: 10.14 g, 92% of theory. dissolves The precipitate (desired product) is filtered off washed three times with diethyl ether dried The combined mother liquors are concentrated under reduced pressure refluxed for 13 h (the precipitate dissolves The precipitate (desired product) is filtered off washed three times with diethyl ether dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A. Gutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and 4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water (9:1, 140 ml) is refluxed for 14 h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. The combined mother liquors are concentrated under reduced pressure and, after addition of a second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (2.84 g, 14.0 mmol), suspended in ethanol/water (9:1, 70 ml) and refluxed for 13 h (the precipitate dissolves, after some time again formation of a precipitate). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. Total yield: 10.14 g, 92% of theory. dissolves The precipitate (desired product) is filtered off washed three times with diethyl ether dried The combined mother liquors are concentrated under reduced pressure refluxed for 13 h (the precipitate dissolves The precipitate (desired product) is filtered off washed three times with diethyl ether dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A suspension of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione (A. Gutcait et al. Tetrahedron Asym. 1996, 7, 1641) (5.68 g, 27.9 mmol) and 4-(4-aminophenyl)-3-morpholinone (5.37 g, 27.9 mmol) in ethanol/water (9:1, 140 ml) is heated under reflux for 14 hours (the precipitate dissolves; after some time, another precipitate is formed). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. The combined mother liquors are concentrated under reduced pressure and, after addition of a second portion of 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3-(2H)-dione (2.84 g, 14.0 mmol), suspended in ethanol/water (9:1, 70 ml) and heated under reflux for 13 hours (the precipitate dissolves; after some time, another precipitate is formed). The precipitate (desired product) is filtered off, washed three times with diethyl ether and dried. Total yield: 10.14 g, 92% of theory. under reflux for 14 hours (the precipitate dissolves after some time, another precipitate is formed) The precipitate (desired product) is filtered off washed three times with diethyl ether dried The combined mother liquors are concentrated under reduced pressure heated under reflux for 13 hours (the precipitate dissolves after some time, another precipitate is formed) The precipitate (desired product) is filtered off washed three times with diethyl ether dried